diagnostic pathology of tumors of peripheral nerve

NEUROPATHOLOGY REVIEW SERIES

Diagnostic Pathology of Tumors of Peripheral Nerve

Sarra M. Belakhoua, MD∗ ‡

Fausto J. Rodriguez, MD ∗§ ¶

∗Department of Pathology, JohnsHopkins University School of Medicine,Baltimore, Maryland, USA; ‡School ofMedicine, University of Tunis El Manar,Tunis, Tunisia; §Department of Ophthal-mology, Johns Hopkins University Schoolof Medicine, Baltimore, Maryland, USA;¶Sydney Kimmel Cancer Center, JohnsHopkins University School of Medicine,Baltimore, Maryland, USA

Correspondence:Fausto J. Rodriguez, MD,Johns Hopkins University School ofMedicine,Sheikh Zayed Tower, RoomM2101,1800 Orleans St,Baltimore, MD 21231, USA.Email: [email protected]

Received,May 15, 2021.Accepted, September 9, 2021.Published Online, February 16, 2021.

C© Congress of Neurological Surgeons2021. All rights reserved.For permissions, please e-mail:[email protected]

Neoplasms of the peripheral nervous system represent a heterogenous group with awide spectrum of morphological features and biological potential. They range frombenign and curable by complete excision (schwannoma and soft tissue perineurioma)to benign but potentially aggressive at the local level (plexiform neurofibroma) to thehighly malignant (malignant peripheral nerve sheath tumors [MPNST]). In this review,we discuss the diagnostic and pathologic features of common peripheral nerve sheathtumors, particularly those that may be encountered in the intracranial compartmentor in the spine and paraspinal region. The discussion will cover schwannoma, neurofi-broma, atypical neurofibromatous neoplasms of uncertain biological potential, intra-neural and soft tissue perineurioma, hybrid nerve sheath tumors, MPNST, and the recentlyrenamed enigmatic tumor, malignant melanotic nerve sheath tumor, formerly referred toas melanotic schwannoma. We also discuss the diagnostic relevance of these neoplasmsto specific genetic and familial syndromes of nerve, including neurofibromatosis 1, neurofi-bromatosis 2, and schwannomatosis. In addition, we discuss updates in our understandingof the molecular alterations that represent key drivers of these neoplasms, includingneurofibromatosis type 1 and type 2, SMARCB1, LZTR1, andPRKAR1A loss, aswell as the acqui-sitionofCDKN2A/Bmutations andalterations in thepolycomb repressor complexmembers(SUZ12 and EED) in the malignant progression to MPNST. In summary, this review coverspractical aspects of pathologic diagnosis with updates relevant to neurosurgical practice.

KEY WORDS: Neurofibroma, Schwannoma, MPNST, Neurofibromatosis, Schwannomatosis, Schwann cell, NF1,NF2, SMARCB1, LZTR1, PRKAR1A

Neurosurgery 88:443–456, 2021 DOI:10.1093/neuros/nyab021 www.neurosurgery-online.com

T he peripheral nervous system is composedof peripheral nerves and ganglia, whicharise from the brain stem or the spinal

cord and course throughout the body to reach itsvarious targets. Its function is to provide somaticand autonomic innervation. The peripheralnerves are formed by bundles of axons and aredefined at the microscopic level by myelinationmediated by Schwann cells. Peripheral nerves arecomposed of organized specialized tissue forming3 layers: the endoneurium, the perineurium,and the epineurium (Figure 1). The anatomicaldistribution and histological complexity of the

ABBREVIATIONS: ANNUBP, atypical neurofibro-matous neoplasms of uncertain biological potential;EBV, epstein barr virus; EMA, epithelial membraneantigen; GTP, guanosine triphosphate; HPFs, highpower fields; MMNST, malignant melanotic nervesheath tumor; NFP, neurofilament protein; PRC,polycomb repressive complex

CNS Spotlight available at cns.org/spotlight.

peripheral nervous system is reflected in themorphological and biological heterogeneity ofthe tumors that arise or differentiate toward itsvarious cell components. Tumors of peripheralnerve range from benign to highly malignant.Comprehensive molecular genetic profiling

using high resolution platforms is currentlytransforming the approach to pathologicdiagnosis of disease and cancer, includingperipheral nerve sheath tumors (PNSTs).Well-defined morphological criteria still allowfor classification in most cases, but globalmethylation profiling1 in tumor and next-generation sequencing platforms in tumor andblood2,3 may provide additional diagnosticand prognostic information. Although PNSTsusually develop sporadically in patients lackinga familial history or genetic predisposition, theyare important components of a variety of geneticsyndromes and pathologic characterizationconstitute important diagnostic criteria withconsequences for clinical follow-up and geneticcounseling. These syndromes mainly include

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BELAKHOUA AND RODRIGUEZ

FIGURE1. Microanatomy of peripheral nerve. The peripheral nerve is composed of epineurium surroundingindividual units (fascicles, in light green). The various nerve sheath tumors share phenotypic propertieswith the non-neoplastic cell components illustrated, predominantly with Schwann cells. Perineurial cellsform the perineurium surrounding individual fascicles and have phenotypic overlap with the neoplastic cellsof perineurioma. A variety of mesenchymal cells populate the epineurium, and although rare, there is awide morphological and biological variation in the group of soft tissue neoplasms that may also involve theperipheral nerve as a primary site. Note that the phenotypic overlap of neoplasms with non-neoplastic cellcounterparts does not imply that the latter are the cell of origin for the related neoplasms. In experimentalmodels, cells of origin tend to be stem cell/progenitor cell precursors.

neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2),schwannomatosis, and Carney complex4 (Figure 2).

In this review, we focus on the major categories of PNST thatare likely to be encountered in neurosurgical practice. We focuson those that develop predominantly intracranially and in spinalnerve roots (Table). Key histologic and molecular genetic featuresthat are useful for diagnosis are particularly emphasized.

SCHWANNOMA

Schwannomas are benign nerve sheath tumors composed ofneoplastic Schwann cells. They develop at multiple body sitesbut intracranially they favor the vestibular branch of the VIIIcranial nerve. On imaging, they present as masses of the cerebel-lopontine angle (Figure 3). As discussed below, bilateral vestibularschwannomas are diagnostic of NF2.5 Schwannomas may alsoinvolve other cranial nerves and in rare occasions be entirely intra-parenchymal within the brain.6 Grossly, they are usually solitary,and the cut surfaces display a light-tan appearance surroundedby a fibrous capsule. A yellow color is frequent because of lipidcontent or lipid-laden macrophages. Variably sized cysts andhemorrhagic changes may be present. Histologically, in theirclassic form, schwannomas contain compact patterns (AntoniA), alternating with loose patterns (Antoni B). The AntoniA zones are characterized by increased cellularity and spindle

nuclei. These zones are studded with clumps of cellular aggre-gates, where palisading patterns called Verocay bodies may beencountered, which are almost diagnostic at the histologic level(Figure 3). Paradoxically, Verocay bodies are frequently absentin vestibular schwannomas. The Antoni B zones are disorga-nized arrangements that are hypocellular and feature a variablemacrophage infiltrate. The surrounding capsule is formed bymultiple layers of collagen fibers. Other common histologicfindings in schwannomas include hyalinized vessels with perivas-cular hemosiderin deposition, cystic spaces, and degenerativeatypia (“ancient change”). Malignant transformation in schwan-nomas is exquisitely rare but usually takes the form of epithelioidmalignant peripheral nerve sheath tumor (MPNST), a round cellmalignancy or angiosarcoma.7,8

On immunohistochemistry, schwannomas are diffuselypositive for mature Schwann cell markers, including S100 andSOX10 protein (Figure 3). Collagen IV and reticulin specialstains are positive around individual cells. Epithelial membraneantigen (EMA) outlines perineurial cells peripherally but isnegative in neoplastic cells. Neurofilament protein (NFP)highlights rare entrapped axons, but these are usually encoun-tered in the periphery. Neoplastic cells in schwannoma alsoexpress vascular endothelial growth factor and antiangiogenictherapy with bevacizumab is often used for progressive vestibularschwannomas in NF2 patients.9

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PERIPHERAL NERVE TUMORS

FIGURE 2. Summary of molecular genetic pathogenesis of nerve sheath tumors. Tumor syndromes of nerve usually develop secondary togermline mutations in several key tumor suppressor genes: NF1, NF2, SMARCB1, or LZTR1 (schwannomatosis) and PRKAR1A (MMNST,in Carney complex). In the context of NF1, mutations associated with tumor progression include CDKN2A (p16) in atypical neurofi-broma/ANNUBP and alterations in members of the PRC 2 (SUZ12 or EED).

TABLE. Peripheral Nerve Tumors Relevant to Intracranial andParaspinal Locations

SchwannomaNeurofibromaPerineuriomaHybrid nerve sheath tumorSchwannoma/perineuriomaNeurofibroma/schwannomaNeurofibroma/perineurioma

ANNUBPMMNSTMPNSTMiscellaneousLipoma of VIII cranial nerveGlomus tumor of nerveSarcomasPrimary central nervous system tumors presenting in nerveroot (myxopapillary ependymoma, hemangioblastoma)LymphomaMetastatic carcinoma

Cellular SchwannomaThis type of schwannoma is composed almost entirely of

Antoni A patterns lacking Verocay bodies (Figure 3). Althoughbenign, it often displays local aggressiveness (eg, bone erosion).Dense cellularity and mitotic activity make this schwannoma

variant particularly prone to be mistaken for malignancy.10Important typical features that help in avoiding this pitfallinclude the presence of a continuous peritumoral capsule, a richmacrophagic infiltrate, and the diffuse expression of Schwann cellmarkers (S100 and SOX10)11 and, in contrast to most MPNST,retain H3K27 trimethylation (or H3K27me3).12 A diffuselymphocytic cuff under the capsule may be present, occasionallycontaining even well-formed lymphoid follicles. It must behighlighted that malignant transformation of schwannoma intoMPNST is exquisitely rare and takes the form of a morpho-logical change (eg, epithelioid, small cell, and angiosarcoma).Therefore, once the neoplasm is identified as a schwannoma,a simple increase in cellularity and/or mitotic activity, in thecontext of the features listed above, should not suggest malignantchange. Cellular schwannomas may be encountered in a varietyof body sites, including paravertebral areas. Involvement ofthe intracranial compartment is rare, but we have recentlyreported our experience with cellular schwannomas in thisanatomic location.13 The intracranial cellular schwannomasmostly developed in association with cranial nerve VIII or V. Localrecurrences developed in a subset of patients, but no metastasesor deaths were documented.

Plexiform SchwannomaThis schwannoma variant has a predilection for superficial

sites, growing mostly in cutaneous or subcutaneous tissues, but


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FIGURE 3. Schwannoma. A, The vestibular branch of cranial nerve VIII is the main intracranial site of origin of schwannoma. B, Antoni A areas are compactand may contain characteristic palisades known as Verocay bodies. C, Antoni B patterns are composed of loose tissue with variable histiocytic infiltrates. Cellularschwannoma is a specific variant that is particularly prone to be mistaken for malignancy.D, Mitotic figures may be encountered (arrow). E, Plexiform neurofibromasare composed of multinodular aggregates of predominantly Antoni A tissue. F, Epithelioid schwannomas are rare, composed of plump cells with prominent nuclei andnucleoli. Strong expression of mature Schwann cell markers is typical of all schwannomas, including S100 G and SOX10 H. I, Patchy loss or a “mosaic” pattern ofINI1/SMARCB1 immunostaining is typical of syndrome-associated (NF2 and schwannomatosis) schwannomas.


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may also develop in major peripheral nerves and plexi.14 Theirdistinctive feature is a plexiform or nodular growth pattern(Figure 3). A capsule is usually absent. Plexiform schwannomasmay be associated with local recurrences, but malignant transfor-mation is exceedingly rare. Most occur sporadically, but a smallsubset (∼5%) develops in genetic syndromes (NF2 or schwanno-matosis). Other rare schwannoma variants include epithelioid,15neuroblastoma-like,16 and reticular.17

Molecular GeneticsOne important aspect of the diagnostic pathology of schwan-

nomas is that when multiple, they are an important componentof NF2 and schwannomatosis, and they represent importantdiagnostic criteria for these syndromes.5,18 The hallmark of NF2is the presence of bilateral vestibular schwannomas. Additionally,these patients develop other tumor types, particularly menin-giomas and ependymomas. Approximately half of NF2 patientshave a familial history. Schwannomatosis is sporadic in mostinstances (75%-85%), with approximately 15% to 25% beinginherited. These patients almost exclusively develop schwan-nomas, but in rare instances, they also develop meningiomas.19,20Although schwannomas developing in genetic syndromes andsporadically are indistinguishable in most instances, featuresoverrepresented in syndrome-associated cases, include whorlingpatterns, myxoid change, nerve edema/infiltration, and a mosaicpattern of SMARCB1/INI1 loss by immunohistochemistry.21The exception is NF2-associated vestibular schwannomas, whereSMARCB1/INI1 positivity remains intact.22A loss of function mutation in the NF2 gene is the most

common genetic feature of schwannomas in sporadic and familialforms. The NF2 gene is located at the 22q12.2 chromosomallocus and encodes Merlin. Merlin is known to interact withcell junctional complexes and plays a role in contact-dependentinhibition. It has multiple additional cellular functions, includingactivation of oncogenic signaling pathways. Recent geneticprofiling studies of schwannomas have also found recurrentmutations in ARID1A, ARID1B, and DDR1 as well as anovel SH3PXD2A-HTRA1 fusion in subsets of schwannoma.23Germline NF2 mutations are diagnostic of NF2 syndrome.The germline alterations responsible for schwannomatosis areunknown in most instances, but SMARCB1 (Chr 22q11.23locus)24 or LZTR1 (Chr 22q11.21 locus)25 germline mutationsoccur in subsets. SMARCB1 is a component of the switch/sucrosenonfermentable (SWI/SNF) chromatin remodeling multiunitcomplexes that are Adenosine triphosphate dependent andmediate changes in chromatin architecture and gene expression.LZTR1 encodes the leucine zipper-like transcription regulator 1,a member of the BTB-kelch superfamily. LZTR1 is a Golgicomplex protein and interacts with the CUL3-based ubiquitinligase complex. In addition to schwannomatosis, this gene has alsobeen found to be altered in Noonan syndrome and glioblastoma,and may participate in the regulation of RAS/MAPK signaling.26

Schwannomas developing in the context of SMARCB1-associated schwannomatosis represent an illustrative model onthe cooperation of tumor suppressor loss in human neoplasia. Inthis context, the sequence involves a “four-hit” event in whichsequential inactivation of both copies of SMARCB1 and NF2occur in the individual tumors.24 This event is probably facili-tated by the localization of both genes in the chromosome 22qarm.

NEUROFIBROMA

Neurofibroma is another benign tumor composed of neoplasticSchwann cells, but unlike schwannoma, it also contains additionalnon-neoplastic components, including fibroblasts, mast cells,perineurial-like cells, and residual axons. Sporadic cutaneousneurofibroma is the most common subtype. However, multipleneurofibromas are a key feature of NF1, in which there maybe involvement of multiple cutaneous sites, peripheral nerves,and spinal roots (Figure 4). Gross examination of neurofibromasinvolving peripheral nerves demonstrate fusiform enlargement ofthe parent nerve fascicle. Cut surfaces are variably yellow andtranslucent depending on the extent of myxoid stroma. The histo-logic features of neurofibroma are similar independent of specificsubtype, and include a predominance of Schwann cells with thinwavy nuclei embedded in a myxoid matrix with variable amountsof collagen arranged in a haphazard fashion (Figure 4). Other cellcomponents that are present in variable amounts include mastcells, lymphocytes, fibroblasts, and EMA-positive perineurialcells that all contribute to the tumor microenvironment. Wheninvolving nerve roots in the spine, neurofibromas may entrapganglion cells through infiltration of sensory ganglia. In contrastto schwannoma, entrapped axons are frequent in the substance ofthe neoplasm because it is more infiltrative and, therefore, morechallenging to resect without affecting the parent fascicle. Theimmunophenotype is characterized by uniform S100 and SOX10expression in the neoplastic Schwann cells, whereas EMA labelsperineurial cells and CD34 stromal cells. NFP typically outlinesnumerous entrapped axons.

Diffuse NeurofibromaDiffuse neurofibromas typically form plaque-like enlargements

of the skin and underlying subcutis. Approximately 10% ofcases develop in NF1 patients. They lack a capsule and arepoorly demarcated. These tumors may entrap adnexal and under-lying soft tissue structures and frequently contain pseudomeiss-nerian corpuscles (spherical arrangements of S100-positive cellprocesses) (Figure 4). Transformation into MPNST in diffuseneurofibromas is rare, compared to plexiform and intraneuralneurofibromas, but well documented.27

Plexiform NeurofibromaPlexiform neurofibroma is a neurofibroma variant defined

at the architectural level as involving multiple peripheral nervefascicles, and therefore, it is frequently associated with larger


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FIGURE 4. A, Neurofibroma. Multiple neurofibromas involving cervical nerve roots in a patient with NF1. Neurofibromas are composed of wavy nuclei, somewhatsmaller than those of schwannoma, with associated delicate collagen B and variable myxoid stroma C.D, Plexiform neurofibromas are typical NF1-associated tumorsand form multiple tortuous nodules, reflecting multifasicular involvement best appreciated at low power. E, Diffuse neurofibromas may be infiltrating, frequentlyentrapping adnexal structures (arrow) and containing characteristic pseudomeissnerian corpuscles (asterisks). Massive soft tissue neurofibromas are typically enormousneoplasms, developing exclusively in NF1 patients. F, A cellular, but benign, round cell component is frequent (arrows).G, Neurofibromas frequently involve the dorsalroots in NF1 patients. Infiltration of dorsal root ganglia should not be mistaken for ganglion cell differentiation. The designation ANNUBP is usually reserved forthe identification of some worrisome histologic features in small biopsies from NF1 patients but not meeting criteria for malignancy. H, This example demonstrateshypercellularity and nuclear enlargement. I, NFP immunostain is useful in highlighting underlying axons in the substance of neurofibromas (arrow).


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nerves and plexi. This subtype frequently affects (20%-50%)patients with NF1,28 representing important clinical criteria forthe diagnosis, and in these patients, it is an important precursorfor MPNST.29 In fact, plexiform neurofibromas involving largenerves and body regions are almost limited to patients satis-fying clinical criteria for NF1. The rare cases lacking otherclinical criteria for NF1 are usually classified as localized or“segmental” NF1. Malignant degeneration of plexiform neurofi-bromas occurs in approximately 5% of cases. In plexiformneurofibroma, the proliferation of Schwann cells involvesmultiple fascicles, englobing long nerve segments (Figure 4).Their distinctive feature is a multinodular enlargement, givingthem the appearance of “bag of worms” or “string of onions.”The histologic features are similar to neurofibromas occurringat other sites; therefore, the imaging, gross appearance, and lowpower histologic features are essential for diagnosis. Plexiform anddiffuse components can co-exist in individual tumors.

Massive Soft Tissue NeurofibromaThis rare neurofibroma variant occurs exclusively in NF1

patients. These tumors are remarkable for their often-colossalsize (which may span an entire limb) and the exquisite infil-tration of local soft tissues, including skeletal muscle and evenbone. They are characterized by slow progression, often beginningin childhood. They arise in subcutaneous tissue and may becovered by hyperpigmented skin.30 Histologically, the tumorsare characterized by extensive infiltration of underlying softtissues, including skeletal muscle. Pseudomeisnerian corpusclesand cellular areas are frequently present (Figure 4).

Molecular GeneticsThe defining genetic event for all neurofibroma subtypes is

inactivation of the NF1 gene (chromosome locus 17q11.2),encoding neurofibromin, a GTPase-activating protein that isexpressed in many cell types in the central and peripheral nervoussystem. It regulates RAS signaling by mediating the conversionof Guanosine triphosphate (GTP)-bound RAS (active) toits Guanosine diphosphate (GDP)-bound state (inactive).31-33GTP-bound RAS results in activation of MAPK, extracellularsignal-regulated kinase 1 and 2 (ERK1 and ERK2), and increasedPI3K-mTOR signaling. The end result is increased transcriptionof target genes, cell growth, survival, and proliferation.34-39 NF1inactivation also results in altered cAMP levels through regulationof adenylate cyclase, which affects non-neoplastic (eg, cognitive)as well as neoplastic manifestations of the disease. NF1 geneinactivation is the sole recurring abnormality in neurofibromas,40with additional alterations acquired as part of atypical andmalignant progression. Of therapeutic relevance, MEK inhibitors(eg, selumetinib) are currently feasible and may provide thera-peutic benefit for some patients with plexiform neurofibroma.41

ATYPICAL NEUROFIBROMATOUS NEOPLASMOF UNCERTAIN BIOLOGICAL POTENTIAL

An atypical neurofibroma category has been controversial giventhe nosologic confusion that it creates and applied in various waysto denote a range of changes ranging from totally benign and clini-cally inconsequential (eg, degenerative atypia or “ancient change”)to low-grade malignant change. Clear-cut diagnostic criteria forthese important changes in the management of neurofibromas,particularly in the context of NF1, are lacking. A recent publishedconsensus42 proposed the designation of atypical neurofibromatousneoplasms of uncertain biological potential (ANNUBP) for a groupof tumors with someworrisome histologic features, but not clearlydeserving a diagnosis of malignancy (Figure 4). Criteria for thedesignation of ANNUBP include neurofibromas with at least 2of the following 4 features: histologic atypia, loss of the typicalneurofibroma architecture, hypercellularity, and increasedmitoticactivity (>1/50 but <3 mitotic figures per 10 High power fields(HPFs) or <1.5 mitoses/mm2). This diagnosis should promptadditional evaluation (eg, tissue sampling) and close clinicalfollow-up. The sequence of molecular alterations responsible formalignant change in NF1-associated tumors is also beginningto be characterized, with premalignant change in neurofibromademonstrating NF1 inactivation, a low mutation burden, andCDKN2A/B loss.43

PERINEURIOMA

Perineuriomas are benign tumors composed of neoplasticperineurial cells. Two types of perineuriomas can be distin-guished: intraneural and soft tissue perineuriomas, dependingon their association to a major nerve or lack thereof, respec-tively. Historically, most cases of intraneural perineurioma wereinterpreted as localized hypertrophic neuropathy, which suggesteda reactive process involving nerve and overlapping with avariety of reactive neuropathies. Immunohistochemical, ultra-structural, and molecular genetic studies have clarified intra-neural perineurioma to be a neoplastic proliferation of perineurialcells rather than a reactive process. Macroscopically, intraneuralperineuromas appear as segmental enlargements of nerve. Histo-logic examination demonstrates multiple concentric cytoplasmiclayers forming whorls of variable size surrounding central axons(“pseudoonion bulbs”)44 (Figure 5). Despite the increased cellu-larity, mitotic activity is low to absent. Immunohistochemicalfeatures include membranous staining with EMA, GLUT-1,and Claudin-1 positivity, whereas S100 is negative, whichdifferentiates neoplastic cells from underlying resident Schwanncells. Residual non-neoplastic Schwann cells and central axonsin the pseudo-onion bulbs are identifiable with S100 andNFP immunoreactivity, respectively. At the molecular geneticlevel, most intraneural perineuriomas have TRAF7 alterations,and a minority has NF2/chromosome 22 alterations.45 Softtissue perineuriomas share the same immunophenotype with


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FIGURE 5. Perineurioma. A, Intraneural perineurioma is a benign nerve sheath tumor characterized by the formation ofpseudo-onion bulbs composed of neoplastic perineurial cells best appreciated on cross sections. B, Longitudinal sections mayappear hypercellular, but the neoplasms are uniformly benign. Soft tissue perineuriomas form solid masses typically unassociatedwith major nerves. C, A storiform pattern is typical. EMA expression is typical of all perineurioma subtypesD, although it maybe weak or focal.

intraneural perineuriomas, but they form well-circumscribedmasses unassociated with major nerves.46 Molecular genetic alter-ations reported include deletions involving theNF1 orNF2 locusin a mutually exclusive fashion.47 A few cases of intracranialperineuriomas have been reported, related to dura48 or inside theventricles.49

HYBRID NERVE SHEATH TUMORS

It has been increasingly recognized that a subset of benignnerve sheath tumors remains difficult to classify and place inone category because they have features of more than onerecognized subtype (Figure 6). The most frequent variety is

schwannoma/perineurioma, which more commonly occurs inthe extremities in the form of subcutaneous/dermal masses.The neoplastic cells show a schwannian morphology, but theoverall architecture resembles that of soft tissue perineuriomas.On immunohistochemistry, all tumors are positive for S100 andEMA.50

Another hybrid combination is neurofibroma/schwannoma,which may involve larger peripheral nerves, and appears to beoverrepresented in patients with genetic syndromes (schwanno-matosis, NF1, and NF2).51 Monosomy 22 is frequent in thesetumors.52 Recently, recurrent ERBB2 mutations were identifiedin a subset of hybrid neurofibroma/schwannomas developing inthe context of schwannomatosis.53


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FIGURE 6. Hybrid nerve sheath tumors. It is increasingly recognized that a subset of benign nerve sheath tumors may contain components of more than 1 tumor type.A, Hybrid schwannoma-perineurioma is the most frequent hybrid nerve sheath tumor. B, Schwannoma-neurofibroma usually takes the form of schwannian nodules(asterisk) in a plexiform neurofibroma background. Hybrid neurofibroma-perineurioma with neurofibroma C and perineuriomaD components highlighted by S100E and EMA immunostains F, respectively.

The least common variation is neurofibroma/perineurioma,the recognition of which is often done through immuno-histochemistry, which highlights EMA-positive areas within aplexiform neurofibroma.54

MALIGNANTMELANOTIC NERVE SHEATHTUMOR

Malignant melanotic nerve sheath tumors (MMNSTs) arePNSTs composed of neoplastic Schwann cells with melanocyticdifferentiation. They present as solitary outgrowths bulgingfrom spinal nerve roots and autonomic ganglia, and asubset is associated with Carney complex. On gross exami-nation, MMNSTs form well-circumscribed, heavily pigmentedtumors, with central necrosis and hemorrhage variably present.Histopathology shows a mix of spindled and epithelioidneoplastic cells arranged in fascicular patterns (Figure 7). Eachneoplastic cell contains multiple intracytoplasmic brown inclu-sions corresponding to melanosomes. The nuclei are roundand uniform with small nucleoli. A subset contains psammomabodies, half of which have been associated with Carneycomplex in historic series,55 but contemporary series havenot found clinical differences between psammomatous andnonpsammomatous subtypes.56 This syndrome is also charac-terized by endocrine hyperactivity, patchy skin hyperpigmen-tation, and a variety of tumor types, including cardiac myxomas.

On immunohistochemistry, MMNSTs are positive for bothSchwann cell and melanocytic markers, including S100, SOX10,melan-A, and HMB45. Collagen IV tends to outline tumorlobules. Molecular genetic studies of these tumors (sporadic andsyndrome associated) have demonstrated frequent loss of functionmutations in PRKAR1A57 located on the chromosome locus17p22-24. There is an additional, less-well-characterized locuson 2p16 that is responsible for a minority of Carney complexcases. Loss of the protein product of PRKAR1A can be detectedthrough immunohistochemistry, which has diagnostic value. Themutations take the form of single base pair substitutions, deletionsand insertions, or rearrangements.58 PRKAR1A is one of themainregulatory subunits that form the Protein kinase A holoenzyme,and loss results in an increase in cAMP signaling.The clinical course of MMNSTs historically has been hard

to predict, and the tumors were formerly designated melanoticschwannoma, given the usual well-developed mature Schwanncell phenotype. However, Torres-Mora et al56 reported high recur-rence and metastatic rates in these tumors, justifying their reinter-pretation as malignant neoplasms.

MALIGNANT PERIPHERAL NERVE SHEATHTUMORS

MPNST are usually high-grade malignant spindle cellneoplasms arising in association with nerves, in pre-existing


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FIGURE 7. MMNSTs. A, MMNSTs are distinctive nerve sheath neoplasms with conspicuous pigmentation that frequently involve nerve roots, ganglia (arrowsindicating entrapped ganglion cells) and autonomic nerves. The tumors may be composed of epithelioid cells with macronucloli forming nests B or spindle cells C. D,Areas of decreased pigmentation may be encountered. E, NFP helps in outlining the axons in the presumed parent nerve. F, Collagen IV may be useful in outliningbasal lamina deposition, a feature of Schwann cells.

Schwann cell neoplasms (most frequently a plexiform neurofi-broma) and/or demonstrating a variable Schwann cell phenotype(Figure 8). They are aggressive tumors characterized by a tendencyto invade surrounding soft tissue and potential for hematogenousmetastatic spread. MPNST can develop in association with NF1,after radiation exposure, or arise sporadically. Macroscopically,MPNST present as adherent, exophytic masses. They have a largevariability in terms of size and consistency, ranging from micro-scopic change in a pre-existing neoplasm to massive tumors. Areasof necrosis and hemorrhage are common. Microscopically, theyare usually cellular neoplasms composed of spindle-shaped cellswith tapered nuclei. They frequently have alternating hyper- andhypocellular areas, which impart a marbled appearance at lowpower. Brisk mitotic activity and necrosis are frequent. Perivas-cular aggregates with herniation inside the vascular lumen are acharacteristic feature. A small subset of MPNST is consideredlow grade, a designation usually applicable to areas of malignantchange within plexiform neurofibromas in NF1.Immunohistochemical stains demonstrate variable S100

and/or SOX10 expression, which is decreased in comparisonwith schwannomas, and maybe altogether negative.11 MPNSTalso demonstrate loss of neurofibromin expression and H3K27trimethylation. The latter is a key epigenetic marker that is lostin MPNST and has relatively high specificity for the diagnosis.12However, close mimickers such as melanoma may also demon-strate loss.59

As mentioned above, most MPNST are high grade and easilyrecognized as malignant at the histologic level. The diagnosisof low grade MPNST is usually made in the context ofNF1-associated neurofibromas with areas of ANNUBP transi-tioning to low grade MPNST. Although difficult to define,proposed criteria include the presence of changes typicalof ANNUBP but, in addition, greater increases in mitoticactivity (1.5-4.5 mitoses/mm2) or 3 to 9 mitotic figuresper 10 HPFs and no necrosis.60 High-grade MPNST arecharacterized by increased mitotic activity, and necrosis isfrequent.MPNST typically develop in association with larger nerves and

plexiform neurofibromas. Rarely they may develop in associationwith cranial nerves and/or in the intracranial compartment.61 Ina series of 17 cases, the vestibular nerves were most commonlyinvolved, and the tumors were aggressive as those occurring inother sites. Careful consideration must be given to exclusion ofdesmoplastic/spindle cell melanoma, a more common diagnosisin head and neck sites.The morphological spectrum of MPNST is remarkable.

Heterologous differentiation may present with a varietyof morphologies, including cartilage, bone, skeletal, andsmooth muscle. Glandular differentiation is a rare butwell documented phenomenon. Other MPNST variantsinclude epithelioid MPNST and MPNST with perineurialdifferentiation.


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FIGURE 8. MPNSTs. MPNST are usually high-grade neoplasms that may arise in a neurofibroma precursor (asterisks) A and are characterized by hypercellu-larity/nuclear atypia B and frequent necrosis C. D, Epithelioid MPNST is a distinctive subset characterized by neoplastic cells with large nuclei with macronucleoli.MPNST developing in a pre-existing neurofibroma (asterisks) E and displaying low-grade histology, including lesser cell density and rare mitotic figures (arrow) F.MPNSTs typically have decreased expression of mature Schwann cell markers, including S100 G and SOX10 H, and in fact may be completely negative. Loss ofH3K27 trimethylation (H3K27me3) is a relatively specific feature. I, Retained positivity in underlying endothelial cells is a useful internal positive control (arrows).


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FIGURE 9. Miscellaneous tumors of peripheral nerve. A variety of soft tissue neoplasms may develop in association with a major nerve or nerve root. A, Lipoma ofcranial nerve VIII with associated entrapped ganglion cells (arrow). Synovial sarcoma is a malignant difficult mimic of nerve sheath tumors when arising primarily innerve. B, The distinction may require molecular testing. C, Smooth muscle tumors may also involve peripheral nerve occasionally. D, This example developed in animmunosuppressed patient and was EBV associated (in Situ hybridization study for EBV encoded ribonucleic acid). Diffuse large B-cell lymphoma may present as aperipheral nerve infiltrate overriding axons E, and is typically outlined by CD20 immunostain F.

Molecular GeneticsIn MPNST germline or acquired NF1, inactivation is

considered an important initiating event, which is followed bya cascade of other mutations that contribute to the malignantphenotype.CDKN2A inactivation and somatic mutations in members of

the polycomb repressive complex (PRC) SUZ12 and/or EED areadditional important events.62,63 The mutations in PRC compo-nents lead to loss of H3K27 trimethylation, which is more typicalof high-grade tumors.

MISCELLANEOUS

A variety of benign and malignant neoplasms may involveperipheral nerves, both intracranially and at spinal/perispinalsites. They vary from rare (lipoma) to relatively more frequent(metastatic carcinoma/melanoma).Lipoma of the 8th cranial nerve is a unique benign lesion

that differs from lipomas arising at other anatomic locations.Magnetic resonance imaging studies are excellent at preoperativediagnosis given the fatty content, which results in hypersensi-tivity on postcontrast T1-weighted images, disappearing on fatsuppression. These lesions are composed predominantly of fat(Figure 9), but other mesenchymal components may be encoun-tered such as smooth or skeletal muscle.

Myxopapillary ependymoma, hemangioblastoma, andparaganglioma are usually considered tumors of the centralnervous system, but they can present as purely involving the spinalnerve roots. A variety of sarcomas may involve the paraspinalregion, nerve roots, and major nerves and are important tumorsin the differential diagnosis of MPNST. Leiomyosarcoma mayhave morphological overlap with MPNST and may also expressS100. However, immunohistochemical markers of smoothmuscle are consistently present, such as smooth muscle actin anddesmin. A group of smooth muscle tumors that may also involvethe intracranial compartment and spinal nerve roots in immuno-suppressed patients are the Epstein Barr Virus (EBV)-relatedsmooth muscle tumors (Figure 9). Monophasic synovial sarcomais a more troublesome mimic of MPNST and may present as apurely intraneural mass64 (Figure 9). Cytokeratin and EMA aretypically positive, but they may also express S100 and SOX10.Neurofibromin and H3K27 trimethylation immunoreactivityare usually retained.12,65-68 The identification of SSX1/SSX2gene fusions are diagnostic.69Melanoma, particularly the desmoplastic variant, may be

difficult to distinguish from nerve sheath tumors, and it maybe a mimic of both neurofibroma and MPNST. Prominentneural infiltration (“neurotropic melanoma”) is a well-describedphenomenon, and may in fact be more frequent in head andneck sites than MPNST. Lymphoma, usually the diffuse large


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B-cell type, can present with prominent peripheral nerve or nerveroot infiltration (Figure 9). Carcinoma from a primary site mayalso involve cranial or spinal nerves by direct spread from headand neck sites (eg, squamous cell carcinoma and adenoid cysticcarcinoma) or pelvis (eg, prostatic adenocarcinoma) all the wayup to their point of origin, in addition to involving nerve asmetastatic deposits.

CONCLUSION

The spectrum of neoplasms that may involve the peripheralnervous system is wide, but most primary tumors have a Schwanncell phenotype, at least in part. They range from the most benignto the most malignant tumors encountered in surgical pathology.They also illustrate the value of diagnostic precision in theirpathologic evaluation, even when benign, given their solid placein the diagnostic criteria of importance to the management ofpatients with genetic syndromes.

FundingThis work was supported in part by NIH grant P30 CA006973 to the Sidney

Kimmel Comprehensive Cancer Center (PI: W. Nelson).

DisclosuresThe authors have no personal, financial, or institutional interest in any of the

drugs, materials, or devices described in this article.

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CNS Spotlight available at cns.org/spotlight.

AcknowledgmentsThe authors also thank Rick Tracey from Path Photo Graphic Arts Laboratory,

Department of Pathology, Johns Hopkins Hospital, for assistance with illustra-tions.


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diagnostic pathology of tumors of peripheral nerve

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